Early CAR T Brings Questions of Preferred Bridging in Multiple Myeloma

For patients with early relapsed multiple myeloma who are candidates for chimeric antigen receptor (CAR) T-cell therapy, the time between a relapse and CAR T infusion represent a clinical inflection point. Manufacturing timelines alone can span 6 weeks for ciltacabtagene autoleucel (cilta-cel; Carvykti), and insurance authorization, organ function testing, and apheresis scheduling can extend the wait to 2 to 3 months. The choice of holding and bridging therapy during that interval is not incidental; it can determine whether CAR T works at all.

In a live Case-Based Roundtable event for oncologists in Orlando, Florida, Sikander Ailawadhi, MD, professor of medicine and chair of hematology at Mayo Clinic Florida, reviewed data from the phase 3 CARTITUDE-4 (NCT04181827) and KarMMa-3 (NCT03651128) trials and led a focused discussion on bridging therapy decisions preceding CAR T infusion in early relapsed myeloma.

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CASE SUMMARY

Patient Profile:​

• A 72-year-old man with newly relapsed multiple myeloma presents to the clinic to discuss his next treatment options.
• ECOG performance status, 2; International Staging System (ISS) III/Revised ISS II; cytogenetics notable for 17p deletion​
• ​He previously achieved a complete response with quadruplet frontline therapy, which continued through autologous stem cell transplant and lenalidomide (Revlimid) maintenance.
• He experienced disease relapse after 9 months. ​
• Although he typically prefers to minimize time spent in the hospital and has an hour-long commute to the academic center, he understands that CAR T-cell therapy requires treatment at a specialized facility. He is willing to proceed with CAR T given his aggressive relapse.​

Ailawadhi established the rationale for CAR T in the patient’s situation with reference to updated efficacy data from CARTITUDE-4. In that trial enrolling patients with 1 to 3 prior lines, including a proteasome inhibitor and immunomodulatory drug (IMiD), who were lenalidomide refractory, cilta-cel produced significant improvements in both progression-free survival (PFS) and overall survival (OS) vs standard-of-care therapy at a median follow-up of 33.6 months.¹ He also reviewed KarMMa-3 (NCT03651128), which demonstrated a PFS benefit for idecabtagene vicleucel (ide-cel; Abecma) in patients with 2 to 4 prior lines.² Ailawadhi noted that roughly one-third of CAR T infusions at his institution remain ide-cel, particularly for older or frailer patients, in part because its single-binding B-cell maturation antigen (BCMA)-binding domain is associated with a lower rate of delayed neurotoxicity than cilta-cel’s dual-binding construct.

With the case for CAR T established, Ailawadhi drew a distinction the group found clinically useful: holding therapy, administered before apheresis to control disease without compromising T-cell fitness, and bridging therapy, given after apheresis during manufacturing to prevent deterioration and reduce disease burden before infusion. Both phases require careful agent selection. He emphasized that a minimum-intensity regimen is preferred, enough to control disease but not enough to produce cytopenias or other adverse events that delay the next step. High-dose cytotoxic chemotherapy before apheresis or bridging should be avoided, as it impairs T-cell yield and CAR T outcomes. A 1- to 2-week washout before both apheresis and infusion is recommended.³ Critically, BCMA-directed agents should not be used as bridging or holding therapy before BCMA-targeted CAR T.⁴

Ailawadhi described a patient whose local oncologist initiated teclistamab (Tecvayli) while waiting for insurance authorization. “I think that is a problem, because the teclistamab is going to downgrade…the BCMA so much that when I give the CAR T, there won’t be enough target available to act,” he said.

Talquetamab (Talvey), which targets GPRC5D rather than BCMA, avoids this concern entirely and was presented as a strong bridging option where accessible. Ailawadhi cited a multicenter retrospective analysis of 134 patients receiving talquetamab as bridging therapy, in which 89% proceeded to CAR T infusion; the reasons patients did not proceed were progression, manufacturing failure, or patient decision. None were drug-related adverse events. Among those who did proceed, the overall response rate (ORR) to CAR T was 88%, with a complete response rate of 54%.⁵ Grade 3 or higher cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) during bridging occurred in 0% and 2% of patients, respectively. Unique toxicities such as oral mucositis (70%), skin changes (38%), and nail changes (17%), were common but resolved in approximately 60% of patients. The practical barrier, Ailawadhi noted, is insurance authorization: talquetamab’s approved indication currently requires 4 or more prior lines of therapy, and most payors deny coverage for second-line bridging use.

For selinexor (Xpovio)-based regimens, the appeal is mechanistic, Ailawadhi said. XPO1 inhibition promotes accumulation of tumor suppressor proteins in the nucleus and drives apoptosis independently of BCMA or T-cell engagement.⁶ He cited data showing that selinexor did not impair T-cell fitness within the bone marrow microenvironment and may even enhance cytotoxic T-cell activity prior to CAR T. In a retrospective cohort of 45 heavily pretreated patients, with a median 7 prior lines before selinexor and 9 before BCMA-directed CAR T, prior selinexor exposure did not compromise subsequent CAR T outcomes, with an ORR to CAR T of 89%, median PFS of 8.0 months, and median OS of 35.9 months.^7,8

He noted that dosing is central to tolerability in the bridging context. Historical trials used selinexor at 80 mg twice weekly; he uses 60 to 80 mg weekly in practice. “It works way better, patients tolerate it way better, and especially in a setting where we need the patient not to be on treatment too long, I think it works out,” he said. Selinexor-carfilzomib (Kyprolis)-dexamethasone (SKd) is his most used bridging combination; selinexor-pomalidomide (Pomalyst)-dexamethasone (SPd) is reserved for patients who require or prefer an all-oral regimen.

When participants were polled on bridging therapy for this specific patient, 45.5% chose a selinexor-based regimen, 27.3% chose an IMiD- or anti-CD38–based regimen, 18.2% chose talquetamab, and 9.1% chose a proteasome inhibitor–based regimen.

When the scenario was reframed for a heavily pretreated patient, selinexor support held (54.5%) while talquetamab gained ground (36.4%), and the IMiD- or anti-CD38–based option dropped to 9.1%.

A majority of participants estimated that only one-half to three-quarters of patients referred for CAR T in their practice ultimately receive infusion. Logistical barriers, including travel burden and caregiver availability, were cited by 83% of the group as the most challenging access factor, a finding that reinforced Ailawadhi’s emphasis on early logistical planning as a component of the CAR T referral itself.

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_{DISCLOSURES: Ailawadhi previously reported consultancy for Celgene, Amgen, Janssen and Takeda, and research funding from Pharmacyclics, Cellectar and Janssen.}

REFERENCES:

1. Einsele H, San-Miguel J, Dhakal B, et al. Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2026;27(2):254-268. doi:10.1016/S1470-2045(25)00653-9

2. Ailawadhi S, Arnulf B, Patel K, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. 2024;144(23):2389-2401. doi:10.1182/blood.2024024582

3. Ailawadhi S, Anderson LD Jr, Dhakal B, Shune L, Sborov DW, Hansen DK. Optimizing selection of bridging therapies prior to CAR-T therapy administration for multiple myeloma: clinical pearls from an expert roundtable. Clin Lymphoma Myeloma Leuk. 2026;26(2):85-93. doi:10.1016/j.clml.2025.08.005

4. Cho SF, Yeh TJ, Anderson KC, Tai YT. Bispecific antibodies in multiple myeloma treatment: a journey in progress. Front Oncol. 2022;12:1032775. doi:10.3389/fonc.2022.1032775

5. Dhakal B, Akhtar OS, Fandrei D, et al. Sequential targeting in multiple myeloma: talquetamab, a GPRC5D bispecific antibody, as a bridge to BCMA CAR-T therapy. Blood. 2025;146(17):2063-2072. doi:10.1182/blood.2025029773

6. Kang Y, Neff JL, Ellero A, et al. Selinexor-based treatments are associated with increased expression of T-cell activation markers in multiple myeloma. Blood Immunol Cell Ther. 2025;1(3):100009. doi:10.1016/j.bict.2025.100009

7. Khouri J, Sborov D, Rossi A, et al. Focusing on selinexor for holding and bridging prior to CAR-T in relapsed/refractory multiple myeloma. J Clin Med. 2025;14(12):4071. doi:10.3390/jcm14124071

8. Costa BA, Dima D, Mark T, et al. Impact of prior selinexor exposure on outcomes of chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma: an exploratory analysis. J Clin Med. 2025;14(4):1316. doi:10.3390/jcm14041316